Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A3 receptor-selective agonists

Article abstract of DOI:10.1016/j.bmcl.2008.04.001

2-Chloro-5′-N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo[3.1.0]hexane) ring system as a ribose substitute display increased selectivity as agonists of the human A₃ adenosine receptor (AR). However, the selectivity in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A₁AR. Therefore, we varied substituents at the N⁶ and C2 positions in search of compounds that have improved A₃AR selectivity and are species independent. An N⁶-methyl analogue was balanced in affinity at mouse A₁/A₃ARs, with high selectivity in comparison to the A_2AAR. Substitution of the 2-chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A₃AR selectivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A₃AR selectivity more effectively than similar chains attached at the 3-position of the N⁶-benzyl group.

Full text of DOI:10.1016/j.bmcl.2008.04.001

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2813–2819
Design of (N)-methanocarba adenosine 50-uronamides as
species-independent A3 receptor-selective agonists
Artem Melman,a Zhan-Guo Gao,a Deepmala Kumar,a Tina C. Wan,b Elizabeth Gizewski,b
John A. Auchampachb and Kenneth A. Jacobsona,*
aMolecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Building 8A, Room B1A-19, Bethesda, MD 20892-0810, USA
bDepartment of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Received 19 February 2008; revised 31 March 2008; accepted 1 April 2008
Available online 4 April 2008
Abstract—2-Chloro-50-N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo[3.1.0]hexane) ring sys-
tem as a ribose substitute display increased selectivity as agonists of the human A3 adenosine receptor (AR). However, the selectivity
in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A1AR. Therefore, we varied substituents
at the N6 and C2 positions in search of compounds that have improved A3AR selectivity and are species independent. An N6-methyl
analogue was balanced in affinity at mouse A1/A3ARs, with high selectivity in comparison to the A2AAR. Substitution of the 2-
chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A3AR selec-
tivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2
position of the purine moiety preserved A3AR selectivity more effectively than similar chains attached at the 3-position of the
N6-benzyl group.
Published by Elsevier Ltd.
Adenosine is a protective mediator that has been de-
scribed as a general endogenous signal for tissue protec-
tion and regeneration and even ‘the signal of life’. 1,2
Adenosine activates four different receptor subtypes—
agonists of the A3AR, IB-MECA 1a and Cl-IB-MECA
1b, are currently in Phase II clinical trials for the treat-
ment of rheumatoid arthritis, several other autoimmune
inflammatory diseases, and cancer.10–12 Protective
mechanisms in the envisioned disease applications of
A3AR agonists appear to be a downregulation of the
NF-jB system, common to both arthritis and cancer
treatments,12 and a widespread correction of gene dys-
regulation induced in an inflammatory bowel model.13
Cardioprotection by selective A3AR agonists has been
extensively explored in various species (Chart 1).14–16
A , A2A, A2B , and A3—which are widely but differen-
1
tially distributed throughout the body.3 The A3 adeno-
sine receptor (AR) is located in some neurons,
astrocytes, various immune cell populations (neutro-
phils, eosinophils, mast cells) and potentially muscle
cells and endothelial cells.4–7 The A3AR is coupled to
inhibition of adenylate cyclase and also activates Akt
and calcium mobilization.8,9 Two potent and selective
Other selective A3AR agonists have recently been
reported, based on the introduction of large substituents
at the N6 and C2 positions and modification of the ri-
bose ring, particularly at the 40 and 50 positions.16–19
For example, the 40-thio analogue 2 is among the most
selective known A3AR agonists,17 and 30-amino substi-
tution is possible.16a Carbocyclic nucleosides have also
been developed as A3AR agonists.20–22 Conformational-
ly constrained methanocarba (bicyclo[3.1.0]hexane)
nucleoside analogues were used to determine that the
biologically active conformation of the ribose ring that
is required in order to bind to and activate the receptor,
Abbreviations: AR, adenosine receptor; CGS21680, 2-[p-(2-carboxy-
ethyl)phenylethylamino]-50-N-ethylcarboxamido-adenosine ; CHO,
Chinese hamster ovary; Cl-IB-MECA, 2-chloro-N6-(3-iodobenzyl)-50-N-
methylcarboxamidoadenosine; CPA, N6-cyclopentyladenosine; DMEM,
Dulbecco’s modified Eagle’s medium; I-AB-MECA, N6-(4-amino-3-iod-
obenzyl)-50-N-methylcarboxamidoadenosine; NECA, 50-N-ethylcarbox-
amidoadenosine; Functionalized congener; Carbocylic.
Keywords: Nucleoside; G protein-coupled receptor; Mouse; Adenosine
receptor; Radioligand binding.
*
Corresponding author. Tel.: +1 301 496 9024; fax: +1 301 480
8422; e-mail: kajacobs@helix.nih.gov
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2008.04.001

2814
A. Melman et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2813–2819
I
the human A3AR of similar derivatives in the ribose
series,18 was prepared by the substitution of the 6-Cl
of 20 with O-methylhydroxylamine followed by the
deprotection of the 20 and 30 hydroxyl groups.
HN
N
N
N
N
O
1a X = O, R = H IB-MECA
1b X = O, R = Cl Cl-IB-MECA
R
X
CH3
Some of the 2-alkynyl derivatives contained chemically
functionalized, extended alkynyl chains to serve as
functionalized congeners for conjugation to other
biologically active moieties or to carriers.27–29 These
included carboxylic acids 18a and 25, amines 18b and
26, and an acetylamino derivative 27. The Sonogoshira
reaction sequence using methyl hexynoate in combina-
tion with an iodo-derivatized nucleoside, either a 2-iodo
(Scheme 1) or N6-(3-iodobenzyl) (Scheme 2) derivative,
provided a mixture of the product methyl ester and
the corresponding carboxylic acid, which were separated
by silica gel column chromatography. The primary
amine congeners 18b and 26 were prepared by the
treatment of the appropriate methyl ester with excess
ethylenediamine.
N
H
2
X = S, R = Cl LJ529
HO
OH
Chart 1. Prototypical selective A3AR agonists.
corresponds to a North (N) conformation. Further-
more, the addition of a 50-N-methyl or ethyl uronamide
group assures that the efficacy of the nucleoside to acti-
vate the A3AR is maintained in combination with vari-
ous structural changes at the N6 and C2 positions, which
modulate the AR selectivity profile and might otherwise
reduce the A3AR efficacy. The conformational flexibility
and H-bonding in the region of the 50-uronamide are
critical factors affecting the efficacy at the A3AR, as de-
duced from structure–activity relationship (SAR) stud-
ies and from rhodopsin-based dynamic molecular
modeling and ligand docking.23
Binding assays were carried out using standard radioli-
gands in Chinese hamster ovary (CHO) cells expressing
the human A1 or A3ARs and in HEK293 cells express-
ing the human A2AAR.22 Also, the mouse ARs were ex-
In this study, we report that certain known A3AR ago-
nists are much less selective at the A3AR in the mouse
than in other species, such as human, and are therefore
unsuitable for use alone as definitive pharmacological
probes in mouse. Thus, additional A3AR agonists dis-
playing high affinity and selectivity that are independent
of species are desired. We previously explored the SAR
surrounding both N6 and C2 positions of 50-N-methyl-
carboxamido adenosine analogues that contained an
(N)-methanocarba ring system as a ribose substitute,
with the objective of designing potent, and selective
A3AR agonists.22 There is a considerable evidence that
appropriate modification of the N6 and C2 positions
of nucleoside agonists is tolerated at the human
A3AR, while SAR at the mouse ARs has not been sys-
tematically explored.3,16–19,23–25
pressed in HEK293 cells for binding assays.15
A
functional assay in guanine nucleotide binding
([35S]GTPcS)20,31 in the membranes of CHO cells
expressing the human A3AR showed that 18a is a full
agonist. The pEC50 value of 18a was 7.85 0.15, in
comparison to the pEC50 value of NECA of 6.46 0.13.
The binding affinity at the mouse and rat A3ARs of the
N6-methyl derivative 3 was considerably weaker than at
the human A3AR (Table 1). Thus, this compound was
balanced in affinity at mouse A1/A3ARs, with high selec-
tivity in comparison to the mouse A2AAR. Other ago-
nists having this mixed AR selectivity were explored
for their cardioprotective properties.29
N6-Benzyl derivatives of adenosine have previously been
shown to favor selectivity at the A3AR.24 This observa-
tion led to the design of 1a and 1b. Although these two
9-riboside derivatives maintain selectivity for the mouse
A3AR, the selectivity in mouse of similar N6-substituted
benzyl (N)-methanocarba derivatives 4–6 was greatly re-
duced due to increased tolerance of this bicyclic ring sys-
tem at the mouse A1AR. Therefore, we varied
substituents at the N6 and C2 positions in an effort to re-
duce affinity at the mouse A1AR. Extension of the 3-
benzyl group as an alkyne in 7 reduced mouse A1 and
A2AAR affinity without greatly reducing affinity at the
mouse, rat, or human A3ARs, resulting in a 57-fold
selectivity for the mouse A3AR. A 2,5-dimethoxy substi-
tution in 8 showed only a slight enhancement of mouse
A3AR selectivity in comparison to 6, the (N)-methanoc-
arba equivalent of Cl-IB-MECA. Modified N6-phenyl-
ethyl analogues 9 and 10, although both very potent at
the mouse A3AR, were essentially nonselective in com-
parison to the mouse A1AR.
Table 1 lists the structures of the adenosine derivatives
that were assayed for binding affinity at ARs from
several species. Compounds 3–12, previously synthe-
sized and evaluated at human and rat ARs,21,22 were
evaluated at the mouse ARs. Based on indications
that the 2-iodo derivative 12 maintained selectivity at
the mouse A3AR, compounds 13–19 and 25–27 were
synthesized. Synthetic routes to the novel derivatives
are shown in Schemes 1 and 2. In the synthetic route
to each of the new A3AR agonists, after the substitu-
tion of the chlorine at C6 in the purine ring of 20 and
21 with a corresponding primary amine R1NH2, the
50-ester group was aminolyzed with methylamine solu-
tion. Resultant compounds of type 22 or 23 were
either hydrolyzed to afford agonists 3–10, 12, 13, 19,
or underwent Sonogashira coupling26 with the corre-
sponding alkynes followed by hydrolysis to afford
agonists 15–17. Agonist 14 was prepared from agonist
15 through desilylation with tetrabutylammonium
fluoride. An N6-methoxy derivative 19, based on a re-
cent report by Volpini et al. showing high potency at
Modification at the adenine C2 position was generally
more beneficial than structural changes of the N6

Table 1. Affinity of a series of (N)-methanocarba adenosine derivatives at three subtypes of ARs in various species
R1
HN
N
N
O
N
R2
N
CH3
N
H
HO
OH
3 – 19, 25 – 27
Compound
R1
R2
Species
Affinity
Selectivity
A1/A3
a
a
a
A1 Ki (nM)
A2A Ki (nM)
(or % inhib.)
A3 Ki (nM)
1a
1b
3
Mb,c
H
5.9
ꢀ1000
0.087
68
49.3 3.7
54
35
93.1 4.2
56
1.74 0.36
1.1
0.18
28d
49
Re
Mb,c
Hd
Re
ꢀ10,000
5400
470
190
160
2500
1.1
220
820
1.4
0.33
CH3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
M
H
55.3 6.0
2100 1700
805g
20,400 3200
(6%)d,f
>10,000g
10,400 1700
2300
49.0 3.9
2.2 0.6
160 30d
1.49 0.46
0.29
950
5.0
R
4h
5
3-Cl–Bn
M
15.3 5.8
260
ND
10.3
900
Hc,d
Rd
M
ND
1.0
3-Br–Bn
8.79 0.12
270
ND
6390 870
1300
ND
0.90 0.22
0.38
0.76
9.8
710
Hc,d
Rc
6h
7
3-I–Bn
M
7.32 1.5
136
83.9g
5350 860
784
0.80 0.14
1.5
1.1
9.2
91
Hc
R
1660g
76
3-(C„C–CH2OH)–Bn
2,5-(OCH3)2Bn
CH2CH(Ph)2
M
111 22
2600 300
ND
(11%)i
1.94 1.1
2.9 0.7
1.6 0.6
1.72 0.04
1.4
57.2
900
Hd
Rd
M
(56%)f
ND
8
29.0 3.3
1600
ND
44,700 5700
ꢀ10,000
ND
17
1100
Hc,d
Rd
M
Hc,d
Rd
M
Hc,d
M
Hd
0.87
1.67 0.09
0.69 0.02
9
6.83 1.5
1300 100
ND
1810 581
1600 100
ND
4.1
1900
10
4
10
c-Pr–Ph
3-Cl–Bn
3-Cl–Bn
Cl
6.60 1.3
770 50
98.9 18.8
610
38,200 5300
4800 200
(32%)i
2.79 0.89
0.78 0.06
1.19 0.09
1.5
2.4
990
83
11
SCH3
I
ꢀ10,000
410
178
610
12h
M
210 34.4
2200
ND
(40%)i
1.18 0.11
3.6
3.9
Hd
Rd
>10,000
ND
(continued on next page)

Table 1 (continued)
Compound
R1
R2
Species
Affinity
Selectivity
A1/A3
a
a
A1a Ki (nM)
A2A Ki (nM)
(or % inhib.)
A3 Ki (nM)
13h
14
2,5-(OCH3)2Bn
I
M
H
293 29
(14%)i
(35%)f
(41%)i
(48%)f
(20%)i
(52%)f
(42%)i
(80%)f
(50%)i
(49%)f
(8%)i
(43%)f
(31%)i
(81%)f
(2%)i
(2%)f
(5%)i
1.51 0.36
1.30 0.27
0.85 0.08
1.30 0.38
4.46 0.57
0.98 0.14
6.06 1.21
0.82 0.20
4.65 0.53
1.17 0.27
24.4 3.1
2.38 0.56
8.60 1.02
2.17 0.51
877 149
149 15
194
2360
53.6
134
35.6
160
229
1300
288
412
431
6260
64
3070 820
45.6 7.9
174 23
3-Cl–Bn
C„CH
M
H
15
3-Cl–Bn
C„C–Si(CH3)3
M
H
159 22
160 40
16
3-Cl–Bn
C„ C(CH2)2–CH3
M
H
1390 430
1040 83
1340 330
482 23
17
3-Cl–Bn
C„C(CH2)3–COOCH3
M
H
18ah
18bh
19
3-Cl–Bn
C„C(CH2)3–COOH
M
H
10,500 1900
14,900 3500
546 62
3-Cl–Bn
C„C(CH2)3–CONH–(CH 2)2NH2
M
H
454 44
209
1.3
OCH3
Cl
Cl
Cl
Cl
M
H
1160 130
265 45
703 71
1.8
49
25
3-(C„C(CH2)3–COOH)–Bn
3-(C„C(CH2)3–CON(CH2)2–NH2)–Bn
3-(C„C(CH2)3–CONH–(CH2)2NH–COCH3)–Bn
M
H
14.4 2.5
17.1 1.2
11.9 2.4
5.21 0.91
4.65 0.22
2.88 0.54
320 31
151 18
(14%)f
(39%)i
(58%)f
(68%)i
(80%)f
19
13
26
M
H
271 23
45.4 3.4
181 22
52
9.8
27
M
H
63
Compounds 1a and 1b are 9-riboside derivatives (Chart 1).
a Competition radioligand binding assays using [125I]N6-(4-amino-3-iodobenzyl)adenosine-50-N-methyl-uronamide (A1 and A3ARs) and [3H]2-[p-(2-carboxyethyl)phenyl-ethylamino]-50-N-ethylcarbox-
amidoadenosine (A2AAR) were conducted with membranes prepared from HEK293 cells expressing recombinant mouse A1, A2A, or A3ARs. At rat and human ARs, the A1 radioligand was either [3H]
R-phenylisopropyladenosine or [3H]2-chloro-N6-cyclopentyladenosine. Values are expressed as means SEM. ND, not determined.
b Data from Ge et al.15
c EC50 value in activation of the A2BAR (human or mouse, as indicated) is P10 lM.15,22
d Data from Tchilibon et al.22
e Data from Kim et al.24
f Percent inhibition at 10 lM.
g Data from Lee et al.21
h 4, MRS3558; 6, MRS1898; 12, MRS3609; 13, MRS5128; 18a, MRS5151; 18b, MRS5166.
i Percent inhibition at 100 lM.

A. Melman et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2813–2819
2817
CH3CH2OCO
O
MeNHCO
O
MeNHCO
HO
N
N
N
N
N
N
a, b
d
O
O
HO
N
Cl
N
NHR1
N
NHR1
20 R2=Cl
21 R2=I
22 R2=Cl
23 R2=I
N
N
N
R2
R2
R2
3
4
5
6
7
8
9
R2 = Cl R1 = Me
c, d
R2 = Cl R1 = 3-Cl-Bn
R2 = Cl R1 = 3-Br-Bn
R2 = Cl R1 = 3-I-Bn
MeNHCO
HO
R2 = Cl R1 = 3-HOCH2C≡C-Bn
R2 = Cl R1 = 2,5-(MeO)2-Bn
R2 = Cl R1 = CH2CHPh2
14 R2 = C≡CH
e
15 R2 = C≡C-SiMe3
N
N
16 R2 = C≡C-(CH2)2CH3
HO
Cl
10 R2 = Cl R1 = 2-Ph-cyclopropyl
12 R2 = I R1 = 3-Cl-Bn
17 R2 = C≡C-(CH2)3CO2CH3
18a R2 = C≡C-(CH2)3CO2H
N
NH
f
N
13 R2 = I R1 = 2,5-(MeO)2-Bn
19 R2 = Cl R1 = MeO
18b R2 = C≡C-(CH2)3CONH(CH2)2NH2
R2
Scheme 1. Synthesis of novel (N)-methanocarba A3AR agonists with structural variation at the 2 and N6 positions. Note that 17 and 18a were both
isolated chromatographically from the same reaction. Reagents and condition: (a) R1NH2; (b) MeNH2, EtOH; (c) RC„CH, PdCl2(PPh3)2, CuI,
DMF, Et3N; (d) TFA, MeOH, H2O, D; (e) TBAF, THF; (f) ethylenediamine, MeOH.
MeNHCO
HO
MeNHCO
O
(CH2)3CO2R
a,b
N
N
C
N
N
HO
O
C
I
N
NH
N
NH
N
N
Cl
Cl
24 R = CH3
25 R = H
6
MeNHCO
HO
(CH2)3CONH(CH2)2NHR
c
N
N
C
24
HO
C
N
NH
N
Cl
26 R = H
27 R = COCH3
d
Scheme 2. Synthesis of novel (N)-methanocarba A3AR agonists containing functionalized alkynyl chains attached at the N6-benzyl 3-position. Note
that 24 and 25 were both isolated chromatographically from the same reaction. Reagents and condition: (a) HC„C(CH2)3COOCH3, PdCl2(PPh3)2,
CuI, DMF, Et3N; (b) TFA, H2O, MeOH, D; (c) ethylenediamine; (d) acetic anhydride.
substituent, with respect to mouse A3AR selectivity. 2-
Cl was replaced with small hydrophobic groups,22
which greatly increased the selectivity for the mouse
A3AR. For example, a 2-iodo analogue 12 was 178-
fold and >180,000-fold selective in binding to the
mouse A3AR in comparison to mouse A1 and
A2AAR, respectively, with a Ki value of 1.18 nM. The
corresponding 2-iodo-N6-(2,5-dimethoxybenzyl) ana-
logue 13 was similarly selective. Thus, the 2-iodo mod-
ification resulted in increased selectivity for the mouse
A3AR; that is, the selectivity ratio of 2-iodo com-
pounds (12 and 13) was increased over that of the cor-
responding 2-chloro analogues (4 and 8, respectively)
by 11- to 17-fold. Other hydrophobic substituents at
the C2 position, such as an ethynyl group in 14 and
its trimethylsilyl adduct 15, provided moderate mouse
A3AR selectivity. Flexible, extended ethynyl chains in
16 and 17 increased the ratio of A3AR selectivity.
2-Alkynyl groups were previously reported to enhance
the affinity of adenosine derivatives at the rat and hu-
man A3ARs.25,30 Compound 18a, a long chain carbox-
ylic acid congener, and its corresponding methyl ester
17 were highly selective for the mouse A3AR in com-
parison to the A1AR by 431- and 288-fold, respec-
tively. Both compounds had greater A3AR selectivity
than Cl-IB-MECA 1b, although these were less potent.
A primary amino congener 18b displayed moderate
A3AR selectivity, with a Ki value of 8.6 nM. Function-
alized congeners in which a functionalized ethynyl
chain was positioned on the N6-benzyl moiety were
only moderately (a carboxylic acid 25) or weakly
(a primary amine 26 and its acetyl analogue 27) selective
for the mouse A3AR. Thus, the attachment of alkynyl
chains at the 3-position of the N6-benzyl moiety did not
preserve A3AR selectivity as well as the placement of sim-
ilar chains at the adenine C2 position.

2818
A. Melman et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2813–2819
4. Yaar, R.; Jones, M. R.; Chen, J.-F.; Ravid, K. J. Cell.
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The use of an alkynyl substituent at the 3-position of an
N6-benzyl group, to serve as a covalent linking site for
conjugation, was shown previously to maintain A3AR
affinity in the series of 9-ribosides.28,29 In the present
study of the (N)-methanacarba series, a variety of aden-
osine derivatives bearing a 2-alkynyl group have been
shown to bind potently and selectively to the A3AR.
7. Platts, S. H.; Duling, B. R. Circ. Res. 2004, 94, 77.
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The (N)-methanacarba derivatives that were most potent
(Ki 1–6 nM) and selective (180- to 290-fold) in binding to
the mouse A3AR were, in order of decreasing affinity: 12,
13, 17, and 16. Compound 18a was the most selective no-
vel agonist in this study at the mouse A3AR; however, the
affinity was intermediate, with a Ki value of 24 nM. The
selectivity for the human A3AR was >6000-fold. Thus,
these C2 position-modified bicyclic nucleosides are good
candidates for species-independent A3AR agonists.
12. Fishman, P.; Jacobson, K. A.; Ochaion, A.; Cohen, S.;
Bar-Yehuda, S. Immunol. Endocr. Metab. Agents Med.
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U.S.A. 1998, 95, 6995.
In conclusion, the selectivity (but not affinity) of (N)-
methanocarba-containing nucleosides as A3AR agonists
was greatly reduced in the mouse due to increased toler-
ance of this ring system at the mouse A1AR. Several
analogues having varied substitution at the N6 and C2
positions were balanced in affinity at mouse A1/
A3ARs, with high selectivity in comparison to the
A2AAR. Substitution of the 2-chloro atom with larger
and more hydrophobic substituents, such as iodo and
alkynyl groups, tended to increase the A3AR selectivity
in mouse and preserve it in human. The carboxylic acid
18a and primary amino 18b derivatives are good candi-
dates for use as functionalized congeners for covalent
conjugation with the retention of biological activity
and receptor selectivity. Thus, we have identified novel
(N)-methanocarba nucleosides that are A3AR-selective
across several species and are especially suitable for
pharmacological studies in the mouse.
15. Ge, Z. D.; Peart, J. N.; Kreckler, L. M.; Wan, T. C.;
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Acknowledgments
This research was supported in part by the Intramural
Research Program of the NIH, National Institute of
Diabetes and Digestive and Kidney Diseases (K.A.J.)
and by NIH R01 HL077707 (J.A.A.). We thank Can-
Fite Biopharma (Petah-Tikva, Israel) for financial
support.
Supplementary data
Supplementary data (chemical synthesis, additional
pharmacological procedures, and functional assay of
18a) associated with this article can be found, in the on-
line version, at doi:10.1016/j.bmcl.2008.04.001.
21. Lee, K.; Ravi, R. G.; Ji, X.-d.; Marquez, V. E.; Jacobson,
K. A. Bioorg. Med. Chem. Lett. 2001, 11, 1333.
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Z. G.; Jacobson, K. A. J. Med. Chem. 2005, 48, 1745.
23. Kim, S. K.; Jacobson, K. A. J. Chem. Inf. Model. 2007, 47,
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